11 beta, 17 alpha-dihydroxypregnan-20-ones and process



the invention is the provision production of 3-substituted-lIBJ'Ya-dihydroXy- Patented Mar. 2, 1954 11 BETA, 17 ALPHA-D 20-0NES A IHYDROXYPREGNAN- ND PROCESS Robert H. Levin, Barney J .Magerlein, and Arthur R. 'Hanze, Kalamazoo, Mich, assignors to The Upjohn Company, ration of Michigan Kalamazoo, Mich, a corpo- No Drawing. Application .March 20,1952,

Serial No. 271724 19 Claims. (Cl. -260--397.45')

The present invention relates to the synthesis of certain steroid compounds, and is more particularly concerned with the novel compounds, Ii-substituted-115,17:-dihydroxypregnan-20-ones, and -to a process for the production thereof.

It is an object of the present invention to provide the novel compounds, 3-substituted-11B,l7adihydroxypregnan-20-ones. A further object of of a process for the pregnan-20-ones. Another object of the present invention is to provide a means, through the formation of a ketal, whereby the 20 position of a 3=substituted-1'Iu-hydroxypregnane-11,20- dione is blocked so that it is non-reactive while .reduction of the ll-ketone is accomplished. Other objects of the invention will be apparent to one skilled in the "art to which'this invention pertains.

The novel compounds of'the present invention may be represented by the following structural formula:

wherein RO-includes the -3aand 3pconfigurations and wherein R is selected from the group consisting of hydrogen and the acyl radical of an organic carboxylic acid, especially such acids containing from one to eight carbon atoms, inclusive.

The novel compounds of the present invention are useful in the synthesis of physiologically active steroids such as cortisone and Kendalls Compound F and are of more general interest in the synthesis of llfi-hydroxy steroids, in addition to having certain physiological activity per :se. For example, Kendall's Compound F acetate is prepared from the 3,1lfl,l7a-trihydroxypregnan-ZO-ones of the present invention by first brominating the 3,11 8,l7e-trihydroxypregnan-20- one, with bromine in chloroform, and then treating the thus-produced 21-bromide with potassium acetate in acetic acid to introduce the ZI-acetoxy group. The thus-obtainedB,llp,l7a-trihydroxyzl-acetoxypregnan-zfi-one is selectively oxidized at the 3-position by an Oppenaur oxidation and containing the resulting B-keto compound is treated with bromine in acetic acid to give the 3-keto-4-bromo derivative, which on treatment with semicarbazidelhydrochloride results in the formation of the S-semicarbazone with elimination of hydrogen bromide to form a double bond between carbon atoms four and five. Removal of the semicarbazone group with pyruvic acid gives Kendalls Compound F acetate. The 3-acy1oxy- 11c,l'ia-dihydroxypregnan-20-ones may be similarly converted to Kendall's Compound F acetate by first saponifying the 3-acyloxy group to a 3-hydroxy group with dilute sodium hydroxide.

The llphhydroxy compounds which are of particular interest are those compounds of the above generic formula wherein R0 represents a 3- hyclroxyl or an ester of the three hydroxy group with an organic carboxylic acid containing up to and including eight carbon atoms. Among such acids are formic, acetic, propionic, butyric, valeric, hexanoic, heptanoic, octanoic, cyclopentanoic, cyclohexanoic, cyclopentylpropionic, benzoic, toluic, and the like.

The novel starting compounds of the invention are the 3-substituted-l'la-hydroxypregnane- 11,20-dione 20-ketals of the following formula:

wherein R0 includes the 311- and 3/3- configurations and wherein R is selected from the group consisting of hydrogen and the acyl radical of an organic carboxylic acid, especially such acids from one to eight carbon atoms, inclusive, and wherein R is selected from the group consisting of hydrogen and lower alkyl groups, especially those containing from one to six carbon atoms, inclusive, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, amyl, isoamyl, hexyl, and the like, and n is an integer from one to two. They are usually obtained by heating a 3-hydroxyor acyloxy-'-17a-hydroxypregnane- 11,20-dione with aketal forming agent, consisting of alkane-1,'2-'diols and alkane-L'3-diols such as, for example, ethylene glycol, propane-1,2- diol, propane-1,3-diol, butane-LZ-diol, pentane- 1,2-diol, S-methylpentane-1,2-diol, hexane-1,3- diol, octane-1,2-diol, and the like, in the presence of an acid catalyst such as, for example, paratoluenesulfonic acid, napthalenesulfonic acid, benzenesulfonic acid, ortho-chlorobenzenesulfonic acid, hydrochloric acid, and sulfuric acid, to convert the 20-ketone to a ZO-ketal, and as more fully described in Preparation 5 through Preparation 13. 3c,1'7adihydroxypregnane-l1,20-dione and 3-esters thereof can be prepared as described by Kritchevsky, Garmaise, and Gallagher in J. Am. Chem. $00., 74, 483 (1952). 3e,1'7a-dihydroxypregnane-l1,20-dione and 3-esters thereof are prepared from the known tip-hydroxypregnane-11,20-dione [Von Euw, Lardon, and Reichstein, Helv. Chirn. Acta., 2'7, 821 (1944)] as described in Preparation 1 through Preparation 1.

According to the novel method of the present invention 3-hydroxyor acyloxy-llslh-dihydroxypregnan-ZO-ones are prepared from starting 3-hydroxyor acyloxy-l'?c-hydroxypregnane- 11,20-dione ZO-ketals by reduction of the 1l ketone group to an ll-hydroxy group using a mixed metal hydride, hydrogen and a catalyst, or other chemical reduction methods, to obtain 3-hydroxyor acyloxy 115,17c dihydroxypregnan-ZO-one ZO-ketals. The Ell-ketal group then is hydrolyzed to obtain a -ketone group and to produce the desired 3-hydroxyor acyloxyl1p,l7e-dihydroxypregnan-20-one.

In carrying out the novel process of the invention a starting 3-hydroxyor acyloxy-17chydroxypregnane-l1,20-dione ZO-ketal is admixed with a solvent which is essentially non-reactive under the reaction conditions employed. The resulting admixture is then subjected to reduction using a mixed metal hydride such as, for example, lithium aluminum hydride, sodium borohydride, lithium borohydride, and the like. Alternatively, other chemical reducing agents, or hydrogen in the presence of a catalyst such as platinum, palladium on charcoal, Raney nickel, and the like, may be used. The exact nature of the solvent used depends in part on the solubility of the starting steroid, the reaction temperature desired, and the reducing agent employed. When mixed metal hydrides are used, solvents such as ether, tetrahydrofuran, benzene,

alkanes, and the like, and sometimes water, are

suitable. When other chemical methods for catalytic methods are used, solvents such as ether, dioxane, alcohol, and the like, and sometimes water, are suitable. In the preferred embodiment of the process, the starting steroid, dissolved in a non-reactive solvent such as, for example, benzene, is admixed with a mixed metal hydride, preferably lithium aluminum hydride, which previously has been admixed with a solvent such as, for example, ether.

During the reduction step the temperature of the reaction mixture is usually maintained be tween about zero and 100 degrees centigrade, with a temperature between about room temperature and the reflux temperature of the reaction mixture being preferred, for a reaction period varying from about one-half to about eight hours or more. When a mixed metal hydride, such as lithium aluminum hydride is used as the reducing agent, the reduction is advantageously first conducted at temperatures between about zero and fifty degrees centigrade, preferably at about room temperature, while during the latter phases of the reaction higher temperatures are utilized, the reflux temperature of the reaction mixture usually being the upper limit. Preferably the reactants are admixed and stirred for about one hour at room temperature and subsequently heated under reflux at the boiling point of the mixture, the total reaction time depending in part upon the ratio of the reactants and in part upon the temperature employed.

Usually a substantial excess of the mixed metal hydride is employed, a one to lOO-fold excess, or more, being operative, with a five to fifty-fold excess being preferred. When hydrogen and a catalyst are used as the reducing agent, the admixture of the starting compound, the solvent, and the catalyst are shaken with hydrogen until the theoretical amount of hydrogen has been absorbed. In most instances reduction using hydrogen at one to three atmospheres pressure at room temperature is entirely satisfactory but higher temperatures and higher pressures of hydrogen are also operative. When lithium aluminum hydride is used as the reducing agent, in addition to reduction of the ll-ketone, the ester group at the 3-position is converted to a hydroxy group. If it is desired to maintain the ester group at the 3-position, other reducing agents such as, for example, sodium borohydride, lithium borohydride or hydrogen with a catalyst may be utilized. Alternatively the product can be reacylated after reduction.

When reduction is substantially complete the excess reducing agent, if any, is destroyed. If a mixed metal hydride or other chemical reducing agent is used, such as, for example, lithium aluminum hydride, the excess lithium aluminum hydride is decomposed by adding, usually dropwise with stirring, a reagent such as Water, wet ether, alcohol, alcohol-ether mixtures, aqueous alcohol, dilute aqueous hydrochloric acid, and the like, the reduction product remaining in the organic phase or solution. When catalytic, reduction is used the catalyst is removed from the resulting solution by filtration. If desired, the 3-hydroxyor acyloxy-lIpJ'Ya-dihydrOXypregnan-ZO-one 20-ketal obtained by reduction may be isolated from the resulting organic solution by any conventional procedure such as, for example, by removing the solvent by distillation. Sometimes it is preferred-not to isolate the reduction product since the solution from the reduction is usually of sufficient purity to be used in the second step of the process of this invention.

A solution of the 3-hydroxyor acyloxyl1e,17c-dihydroxypregnan-20-one ZO-ketal d-issolved in an organic solvent such as those used previously during the reduction, which may be the solution obtained from the reduction step after removal of the catalyst or excess reducing agent, is admixed with hydrolyzing agent. Usually an excess of a dilute aqueous solution of a mineral acid such as sulfuric acid, hydrochloric acid, and the like, is used as the hydrolyzing agent. In some instances acetic acid, other organic acids, other acidic agents, are suitable. A one to lOO-fold excess, or more, of hydrolyzing agent is operative, with a five to ten-fold excess usually being preferred. Usually the reaction mixture is stirred for about 2-: hours at room temperature. The reaction period may be longer or as short as one hour, depending in part on the ketal used, the reaction temperature, and the concentration or" the hydrolyzing agent; Use of higher concentrations of hydrolyzing agent and higher temperatures usually reduces the readmit-99.5

action period. temperatures .ibetween about .zerc srees centigrade :and'abeut the boiling point 01 thereaction mixture being operative. It :is preierred'to stir theozeaction :mixture it consists of inorethan one phase.

When hydrolysis is substantially complete, the product is isolated .by any conventional -.procedure. For example, when :the resulting mixture is composed of -.an organic layer and a. "water :layer, the organic layer is separated, the water layer is extracted with an organic solvent and the extracts combined with the organic layer. The organic phase is then --washed with water and dried using a drying agent such as :anhy .drous sodium sulfate. drying agent and distillation to remove the sol- "vent gives the isolated product. Recrystallization :Irorn any of the common solvents -:results intpurification-of the product.

The following examples ;illustrate the method I and products of the present invention but are not to be construed :as limiting.

PREPARATION 'I.3p-ACETQXYPREGNANE=I1;20-oIoNE iifllydroxypregnane ilLZO-dione (8.18 grams) was dissolved in :a mixture acetic anhydride and two milliliters of pyridine, and the resulting solution was allowed to stand .at .room temperature for 24 hours. The mixture .waSthen poured into .325 milliliters of water and allowed to stand at room temperaturetor-several hours to permit decomposition of the-excessacetic anhydride. The solid product was removedby filtration and dried under vacuum. Two recrystallizations jsrams, melting point 71.55 to 16.2 degrees centigsnade. Repeated recrystall-izationjirom aqueous acetone save 35 acetoxypregnane 1:1,20 dione melting at 164 to 1.65 degrees centigrade; tal plus 99 degrees (chloroform).

Analysis: Percent calculated for-13231113404: C, 73.90,; ,H, 9.10. Found: C, 78.69,; .H, 19.02.

PREPARATION 2-.3/3,11;20-'TRIACETO'XY-9 ('11) ,17(*20) PREGNADIENE A mixture of 2.75 'grams of 2o-acetoxypregnaneallzo dione, 0.73 gram @of para-toluenesulionic acid monohydrate. and ninety milliliters of acetic anhvdride was heated to boiling and allowed to distil slowly for three hours, 7.1 mil liliters .of fifteen milliliters of distillate was collected hi distillation under reduced pressure, and the resulting residue was cooled, diluted with 85 milliliters of ether, washed with one per cent aqueous sodium and dried .cuer anhydrous'sodium sulfate. .Aiter removing the dryingra ent by filtration. theether -=was removed by distillation :gi-ving .;3..-,5 grams of 35,11,20-triacetoxy-9 11) ,17:(,20.) pregnadiehe as a glass.

PREPARATION 3.- .17 hexane-3,8,11,20-rmxcmoxy- 9 11) -1 I tEGNENE The 3.5 greuns oi 35,11.20-t1;iacetoxye9.(1l;)i 17(2m -pregnadiene :irom ,Rreparation -2 was dissolved in seventeen milliliters of chloroform of fifty milliliters of .and the resulting solution cooled :to a tempera :ture oizero to jive degrees eentigrade. A mixture of 170 milligrams of anhydrous sodium acetate and 7.7 milliliters of 38 per cent peracetic acid was added with stirring, the temperature of the reactionmixture-being maintained at-zero to live degrees centigrade. The resulting mix ture was stirred at this temperature for ten. minutes, then allowed to come to room tempera.

Filtration to remove the ,from aqueous acetone gave 2. 75;

distillate being collected. Another.

bicarbonate solution and with "water;

and stirred for an additional ninety min rutes. The mixture then was .di'lutedwith ei hty :milliliters of ether, "washed with four fifteen millillter portions of five per cent aqueous-sodium hydroxide solution and three fifteen-milliliter portions of water, and dried over anhydrous sodium sulfate. Removal of the. drying agent by filtration and distillation of the solvents under reduced pressure :gave 3.5 grams of "1'? (20 )-oxido- 319,1l;20triacetoxy-9 (11)--pregnene as a viscous :oil.

The 17(20) -oxido 35,111.20 triacetoxy-9-fllf)- pregnene from Preparation .3 (3.5 grams) was dissolved in 66 milliliters of alcohol, 66 milliliters of 0.5 normal aqueous sodium hydroxide solution added, and the resulting mixture stirred for thirtyhours at room temperature under a nitro-- gen atmosphere. "The mixture then was poured into 250 milliliters of Water, and the resultant slurry extracted with four fifty-milliliter portions ofchloroform. Distillation of t e extraction solvent gave,2.7.4.grams of crude 3;8,.17a-dihydroxypregnane-1L20-dione. The 3-acetate was prepared byace'tylation with acetic anhydride and pyridine at room temperature. j

RREPARATION 5.3a,17a1nrnrnxoxxrnaeuann-HQO- DIONE 20 ErH-YLEN QLYcoL KETAL L ionic acid monohydrate and milliliters of benzene Was placed in a reaction flask which-was equipped with a reflux condenser'and a water trap so arranged that the condensed vapors passed through the "water trap before re t ming to the reaction flask. The mixture was heated to reflux and was allowed to reflux for five hours while at the same time being a itated. The water which formed was removed by co-distillation with benzene and was collectedin the water trap. The reaction mixture was cooled and poured into a dilute solution of sodium bicarbonate. The benzene layer was separated, washed with water, dried and concentrated to dryness. The residue was chromatographed over forty grams of Florisil (synthetic magnesium silicate) using eighty-milliliter portions of a mixture of ethylene dichloride with successively greaterproportions of acetone for elution. The material whichwas elutedwith cthylen'edichloride-acetone "(12:1 and 8:1) weighed 141 milligrams after removal oi the solvents. Recrystallization 'ofthis material from'benzene-skelly Solve B yielded fifty milligrams of 3e,17a-dihydroxypregnane-l1,20-

dione ZO-ethylene glycol ketal melting at 144 "to Paoranacoron '7 -3a,1711-01HYDROXYPR-EGNANEJLQG- plows 20 BoritNE-1,2-n1or..KETAL 4 "In the same manner as "given in :Preparatioh 5, '-3ml'la-dihydroxypregnane-1 1;20+dione 20 1m- .ylene. glycol. ketalin 7 tane-LZ-diol ketal is prepared from 3a,17adihy droxypregnane-11,20-dione by using butane-1,2- diol instead of ethylene glycol as the ketal forming agent and using sulfuric acid instead of paratoluenesulfonic acid as the catal st.

PREPARATION 8.-301,17nz-DIHYDROXYPREGNAlIE-lLQQ- prom: 1.0- (g-METHYLPENTANE-LQ-DIOL) KETAL of para-toluenesulfonic acid.

PREPARATION 9.-3a,1 'Ta-DIHYDROXYPRBGN sun-11,20- moms 2O-rnoPaN1s-L3-DI0L Kara];

In the same manner as given in Preparation 5, 3a,17a-dihydroxypregnane-11,20-dione ZO-propane-1,3-diol ketal is prepared from 3a,l7a-dlhydroxypregnane-l1,20-dione by using propane-1,3- diol in place of ethylene glycol.

PREPARATION 10.3a-ACETOXY-l7a-HYDROXYPREG- NANE-ILQO-DIQNE QO-ETHYLENE GLYcoL :KETAL In the same manner as given in Preparation 5, 3a. acetoxy-l'la-hydroxypregnane-l1,20-dione ZO-ethylene glycol ketal is prepared from 311- acetoxy-17ahydroxypregnane-1.1.20-dione by reaction with ethylene glycol in the presence of para-toluenesulfonic acid.

PREPARATION 11.-3a-BENzoYLoxY-Ha-HYDnoxYPREG- SANEJLQO-DIONE 20-ETHYLENE GLYCOL KE'PAL In the same manner as given in Preparation 1 5, 3a-benzoyloxy-l'la-hydroxypregnane-11,20-dione 20-ethylene glycol ketal is prepared from 3a.-benzoyloxy-l'la-hydroxypregnane-11,20-dione by reaction with ethylene glycol in the presence of para-toluenesulfonic acid.

PREPARATION l2.3,H.17a-pIHYDRoxYrRnGNANE-11,20- DIONE 2O-ETHYLENE GLYcoL KETAL In the same manner as given in Preparation 5, 3/8,17adihydroxypregnane-l1,20-dione ZO-ethylene glycol ketal is prepared from 3B,].7a-dihY- droxypregnane-11,20-dione by reaction with ethylene glycol in the presence of para-toluenesulfonic acid.

PREPARATION 13.-35-ACETOXY-17a-HYDROXYPPEG- n-l.1,20-DI0NE QO-ETHYLENE GLYCOL KETAL v In the same manner as given in Preparation 5, 3 8 acetoxy-l7a-hydroxypregnane-11,20-dione 20-ethylene glycol ketal is prepared from 3fi-ace- Example 1 .--3u.,1 1 5,1 7e-trihydroxypregnan- 20-one To a solution of two grams of lithium aluminum hydride in 200 milliliters of anhydrous ether was added dropwise, with stirring, two grams of 3a,}.'Ia-dihydroXypregnane-11,20-dione 20-ethtwentymilliliters of anhydrous benzene. The mixture was stirred atro'om temperature for one hour followed by boiling under reflux for an additional hour. With continued stirring thetresulting mixture was cooled and treated cautiously with water added dropwise. The resulting solution, containing. the B lls,17a-trihydroxypregnan-20-one 20-ethylene glycol ketal, was admixed with an excess of dilute hydrochloric acid and the resulting heterogeneous mixture was stirred vigorously for twenty hours at room temperature. The'product was isolated by separating the organic and aqueous layers, extracting the aqueous layer with ether, combining'the ether extract with the organic layer,'washing the organic solution twice with water, drying the washed solution over anhydrous sodium sulfate, removing the drying agent by filtration, and removing the solvents by distilla' tion under reduced presusra' The resulting oily residue was dissolved methyl acetate, and diluted with Skelly Solve B to opalescence. On standing the solution deposited crystals whichw'ere re moved. by filtration and identified as the 1111- isomer 301,1 1e,17a trihydroxypregnan-ZDone) Further dilution of the filtrate with Shelly Solve B gave 590 milligrams of 3e,llfi,'17a.trihydroxy'- pregnan-ZQ-one. an additional quantity of 3a,- l1,8,1'7a-trihydroxypregnan-20-one was obtained from the remaining mother liquor by distillation of the solvents under reduced pressure, redissolving the residual oil in a minimum amount of ethyl acetate, and diluting with SkellySolve B. The 590 milligrams of product was recrystallized once from a mixture of ethyl acetate and Skelly Solve B and once from a mixture of acetone and Skelly Solve B to give 275 milligrams of purified 3a,l1,3,l'h-trihydroxypregnan-20-one as plates; melting point 213 to 216 degrees centigrade; [(13 plus "13 degrees (acetone).

Analysis: Per cent calculated fOI' C21H34O l1 C, 71.9; H, 9.71. Found: C, 72.1; H, 9.81. I

In one experiment, before hydrolysis, the solution containing the 3a,lldl'le-trihydroxypregnan-ZD-one 20-ethylene glycol ketal was dried over anhydrous sodium sulfate, and the ether was distilled. Crystallization of the residue from a mixture of ethyl acetate and Skelly Solve 13 gave 3e,llp,l7a-trihydroxypregnan 20 one 20- ethylene glycol ketal. Hydrolysis of the compound as described above, in ether, gave 3a.,11fi,

17a-trihydroxypregnan-20-one which was identical with that obtained above.

Example Z.3a.,1 15,1 7etrihydroo':ypregnan 7 ZOE-@7113 V Following the procedure given in Example '1, 3a,17a. dihydroxypregnane-11,20-dione 20-ethyl- 'ene glycol ketal is' reduced with lithium bordhydride instead of lithium aluminum hydride,to yield 3a,1is,17a-trihydroxypregnan-20 one} Example 3.--3e-acet0.ry 1balk-dihydrodcypiegnau-ZO-one One hundred milligrams of 3a.,1l;8 ,l7a-trihydroxypregnan-ZO-one was dissolved in'a mixture of 0.5 milliliter of acetic'anhydride and 0.5 milliliter of pyridine, and the resulting solution was allowed to stand at room temperature for sixteen hours. The solution was then poured into a mixture of ice and water and the resulting mixture was allowed to stand for one hour at room temperature to permit decomposition of the excess acetic anhydride. The solid which had precipitated was filtered, washed with water, and dried under vaouum Recrystallization from alcohol gave '75 milligrams of 3 acetoxyl lp, l"l

benzoic anhydride in place of acetic anhydride.

Thesame product is obtained by reducing 30.- benzoyloxy-l 7a-hydroxypregnane- 11,20-dione 2Q- ethylene glycol hotel with sodium borohydride in alcoholand hydrolyzing with hydrochloric acid inv essentially the same manner as described: in Example 1.

Emample 5.-3,11p,17a-trihydroasypregnan -07m- 3a,17a-dihydroxypregnane-Il,20-dione 2'0-pro pane-1,2-dio1 ketal is converted to 3a,I1,B ',I7 trihydroxypregnan-20-one using. lithium. aluminum hydride. in ether followed by hydrolysis of the 311,115 ;'Ta-trihydrOXypregnan-2ll one 2'0-propane-1,2-d'iol ketall with dilute hydrochloric acid as in. Example 1.

Example 6. --3a, 1lp',-17a-trihydroxymregnan- BO-rme- 3%,172 dihydroxypregnane-rmo-dione 20-wtan'e-L2-di'ol ketal is converted to 3a',1lfl,l7w-'tri HydroXypregnaII-ZO-One using lithium aluminum hydride in ether followed by hydrolysis of the 321,11B;l72z-trihydroxypregnan20-one 20-butanef,2-diol ketal as" in Example" 1'; dilute sulfuric acid being" used as the hydrolyzing' agent.

Example 7..3a,11,8,17a-trihydrozzzymegnan- 20-0716 7 3mm --'dihyclroxypregnane l1,20 dione 20-43- methylp'entane-1,2-diol)" ketal is converted to 311',H79;I7a-trihydroxypregn'an20one using sodium Borohydride' in dioxane as. Example-'2, and hydrolyzingwith dilute hydrochloric acid.

E'Immpl 894111131171;-triiiydrolnypigmavt- 20-on'e. 311,17dihydroxypregnane lL,20dione 20-pinpane-lfi-diolr. ketal is converted to 3a,1'1,3;1 ?'a"- triliydroxypregnan-20-one byusing the: procedure of Example 1.

Example 9.3B,11,Bgl7a-triiiydroxymeynafi= Followingthe procedure of Example 1 3,3,17udihydroxypregnane-l1,20-dione ZO-ethylene glycol ketal is reduced. with lithium aluminum hydride: and subsequently hydrolyzed with. dilute sulfuric acid. to" yield 313.11 3,l7a-trihydroxyprege nan-20-one.

prregnando' -one Following the procedure of Example-1, andusing sodium borohydride in dioxan'e as thereducing' agent, 3p-acetoxy-1IBJ'Ia-dihydrOXypregnam v20-o'ne is prepared from 3l9-acetoxy l ia-hydroxypregnanel1-,20--dione 20-ethylene glycol: ketal. Alternatively the same compound-is prepared: by

mixing together a acyloxy l 1 611 7a dihydi'oXypregnan-ZGone with 10 or without-the isolation ofthe intermediate 1 1/3- hydroxy ketals before hydrolysis.

It is to' be understood that the" inventioiiis not to be limited to the exact details ofoperation or exact com-pounds shown and described,

as obvious modifications and equivalents will be apparent to one skilled in the art, and the inventionis therefore to be limited only by thescope of the: appended claims.

We claims 1.= An= 11B,17a-dihydroxypregnan-ZD ane having the following general formula:

wherein R0 includesthe 3a and" 3}9-*corifi'gura'- tion's andwherein R is selected from the group consisting of hydrogen and? the acyl' radical of an unsubstituted monocarboxyiichydrocarbon acid containing from one toeight carbon atoms, elusive.

2. SaulIt;l'fa trihydroxypregnand(Lone.

3. 3w acetoxy 11511711- dihydroxyp'reg'nan zo-one. V

6; A- process for the production of an 111%- di'liydrbz'z'ypre'gnandb=ofie which includes]: (1') mixing together areducing agent" and a flit-KW droxyriregnanedL20 dione zo-ket'al; having a substituent at the 3- osit on or thefor'rnula Rd, B being selected from the group-consisting of hydro en and the acyI radical of an organic monocarboxyuc acidcontaining from one to eignt carbon atoms; inclusive, wherein the Item-group contains the polyme'thylenedioxy radicalof a compound selected from the group consisting of aikane m-dio'ls and alka'ne-lfi -di-ols' containing from two toeig'ht' carbon atoms; inclusive, (2') h'ye drolyzing' the product, and separating thethusproduced 11,17d-dihydroxypregnam2fl=one'.

7. A process for the production of an 11,1 7'Bedihydroxypr'egnan' 20=one which includes: (*1 reducing agent selected from the group consisting" of lithium aluminum hydride, sodium borohydride and lithium boroiiy (hide, and a" 17a-hydroxy-pregiiane=-11,20

substitue'nt at the 3 -nosit1o the formula R0, R being selected from the-group consisting of hydrogen and the acyl' radical. of an organic monocarboxylic acid containing fro'mone to eight' carbonatoms inclusive, Wfifleihififl ketal group contains the polymethylenedioxy radical of a compound selected from the: group consisting of alkane=l,2-diols and: alkane--1 ,3'-diols containing from two to eight carbon atomsyinclusive, 2 Hydihydroxypregnan-ZO-one which includes: mixing together, in an organic solvent which is 1 l drolyzing the product with a mineral acid, and separating the thus-produced l1,l7a-dihydroxypregnan-20-one.

8. A process for the production of an 1113,17adihydroxypregnan-ZO-one which includes: (1) mixing together, in an organic solvent which is non-reactive under the condition of the reaction, a reducing agent selected from the group consisting of lithium aluminum hydride, sodium borohydride and lithium borohydride, droxypregnane-11,20-dione 20-ketal, having a substituent at the 3-position of the formula R0, R being selected from the group consisting of hydrogen and the acyl radical of an organic monocentigrade and the reflux temperature of the reaction mixture, a reducing agent selected from the group consisting of lithium aluminum hydride, sodium borohydride and lithium borohydride, and a 170. hydroxypregnane 11,20 dione 20 ketal,

having a substituent at the 3-po'sition of the formula R0, R being selected from the group consisting of hydrogen and the acyl radical or an organic monocarboxylic acid containing from one to eight carbon atoms, inclusive, wherein the ketal group contains the polymethylen'edioxy radical of a compound selected from the group consisting of alkane-1,2-diols and alkane-1,3-diols containing from two'to eight carbon atoms, inclusive, (2) hydrolyzing the product with a hydrolyzing agent selected from the group consisting of sulfuric acid and hydrochloric acid, and separating the thusproduced 115,17a-dihydroxypregnan-Zfl-one.

10. A process for the production of an 115,17-

non-reactive under the conditions of thereaction and at a temperature between about 'zero degrees centigrade and the reflux temperature of the reaction mixture, a reducing agent selected from the group consisting of 'dride, sodium borohydride and lithium borohydride, and 'a l7a-hydroxypregnane-1-1,20-dione ml-ethylene glycol ketal, having a substituent at the 3-position of the formula R0, R being selected from the group consisting of hydrogen and the acyl radical of an organic monocarboxylic acid containing from one to eight carbon atoms, iniclusive, (2) hydrolyzing the product with a hydrolyzing agent selected from the group consisting of hydrochloric acid and sulfuric acid, and separating the thus-produced 11,6,1'7a-dihydroxypregnan-ZO-one.

11. A process for the production of a 3,1153%- trihydroxy-pregnan-20-on which includes: (1) mixing together, in an organic solvent which is non-reactive under the conditions of the reaction and at a temperature between about zero degrees centigrade and the reflux temperature or the reaction mixture, lithium aluminum hydride, and a I'M-hydroxypregnane-11,20-dione ZO-ketal, havand a 17a-hyinclusive, (2) 1137- the production of an 115,17a-

lithium aluminum hyfrom the group .propane-l,2-diol ketal, (2) not with a hydrolyzing agent selected from the ing a substituent at the 3-position of the formula R0, R being selected from the group consisting of hydrogen and the acyl radical of an organic monocarboxylic acid containing from one to eight carbon atoms, inclusive, wherein the ketal group contains the polymethylenedioxy radical of a compound selected from the group consisting of alkane1,2-diols and alkane-1,3-diols containing from two to eight carbon atoms, inclusive, (2) hydrolyzing the product with a hydrolyzing agent selected from the group consisting of hydrochloric acid and sulfuric acid, and separating th thusproduced 3,11e,l'la-trihydroxypregnan-filfl-one.

12. A process for the production of 3a,llfi,l7atrihydroxypregnan-20-one which includes: (1) mixing together, in an organic solvent which is non-reactive under the conditions of the reaction and at a temperature between about zero degrees centigrade and the reflux temperature of the reaction mixture, lithium aluminum hydride and 311.,1'7a-dihydroxypregnane-ll,20-dione 20- ethylene glycol ketal, (2) hydrolyzing the product with a hydrolyzing agent selected from the group consisting of hydrochloric acid and sulfuric acid, and separating the thus-produced 3a,l1,9,17e-trihydroxypregnan-20-one.

13. A process for the production of 311,115,170.- trihydroxypregnan-20-one which includes: (1) mixing together, in an organic solvent which is non-reactive under the conditions of the reaction and at a temperature between about zero dethe reflux temperature of lithium aluminumhydride and 3d-acetoxy 17a hydroxypregnane-11,20- dione 20-ethylene glycol ketal, (2) hydrolyzing the product with a hydrolyzing agent selected consisting of hydrochloric acid and sulfuric acid, and separating the thus-produced 3a,l1 8,17a-trihydroxypregnan-20-one.

14. A process for the production of 3a,1l 3,17atrihydroxypregnan-ZO-one which includes: (1) mixing together, in an organic solvent which is non-reactive under the conditions of the reaction and at a temperature between about zero degrees centigrade and the reflux temperature of the reaction mixture, lithium aluminum hydride and 3a,17c-dihydroxypregnane-11,20-dione -20- hydrolyzing the prodgrees centigrade and the reaction mixture,

group consisting of hydrochloric acid and sulfuric acid, and separating the thus-produced 3e,11,8,1?a-trihydroxypregnan-20-one.

15. A process for the production of a 3-acetoxy- Hath-dihydroxypregnan 20 one which includes: (1) mixing together, in an organic solvent which is non-reactive under the conditions of the reaction and at a temperature between about zero degrees centigrade and the reflux temperature of the reaction mixture, sodium borohydride and a 3-acetoxy-1'le-hydroxypregnane-11,20-dione 20-ethylene glycol ketal, (2) hydrolyzing the product with a hydrolyzing agent selected from the group consisting oi hydrochloric acid and sulfuric acid, and separating the thus-produced 3-acetoxy-11B,17e-dihydroxypregnan-ZO-one. r

16. In a process for the production of an 11p,1'7a-dihydroxypregnan-20-one, the step of reducing a l'la-hydroxypregnane-11,20-dione 20- ketal, having a substituent at the 3-position of the formula R0, R being selected from the group consisting of hydrogen and the acyl radical of an organic monocarboxylic acid containing from one to eight carbon atoms, inclusive, wherein the ketal group contains the polymethylenedioxy radical of a compound selected from the group consisting of alkane-1,2-diols and alkane-1,3- diols containing from two to eight carbon atoms, inclusive, in a solvent which is non-reactive under the conditions of the reaction, and at a temperature between about zero degrees centigrade and the reflux temperature of the reaction mixture; the reduction being accomplished with a reducing agent selected from the group 0011- sisting of lithium aluminum hydride, sodium borohydride and lithium borohydride.

17. In a process for the production of an 11,9,I'M-dihydroxypregnan-20-one, the step of hydrolyzing an 11,6,I'h-dihydroxypregnan-ZO-one 20-ketal, having a substituent at the 3-position of the formula R0, R being selected from the group consisting of hydrogen and the acyl radical of an organic monocarboxylic acid containing from one to eight carbon atoms, inclusive, wherein the ketal group contains the polymethylenedioxy radical of a compound selected from the group consisting of alkane-1,2-diols and alkane- 1,3-diols containing from two to eight carbon atoms, inclusive, in a solvent which is non-reactive under the conditions of the reaction, and at a temperature between about zero degrees centigrade and the reflux temperature of the reaction mixture; the hydrolysis being accomplished with a hydrolyzing agent selected from the group consisting of sulfuric acid and hydrochloric acid.

18. A process for the production of an 11,17:- dihydroxypregnan-20-one which includes the steps of (l) mixing together an organic ketalforming agent selected from the group consisting of a1kane-1,2-dio1s and alkane-1,3-diols containing from two to eight carbon atoms, inclusive, and a l'la-hydroxypregnane-l1,20-dione, having a substituent at the 3-position of the formula R0, R being selected from the group consisting of hydrogen and the acyl radical of an organic monocarboxylic acid containing from one to eight carbon atoms, inclusive, in the presence of an acid catalyst at a temperature between about twenty and about 200 degrees centigrade, to cause conversion of the 20-keto group to a 20-ketal group, and (2) reducing the ll-keto group of the ketal thus-formed with a reducing agent selected from the group consisting of lithium aluminum hydride, sodium borohydride, and lithium borohydride, in an organic solvent which is non-reactive under the conditions of the reaction at a temperature between about zero degrees centigrade and the reflux temperature of the reaction mixture, and (3) hydrolyzing the reduction product thus-obtained with a hydrolyzing agent, and separating the thus-produced 11,l7a-dihydroxypregnan-20-one.

19. A process for the production of a 3,115,171;- trihydroxypregnan-20-one which includes the steps of 1) mixing together ethylene glycol and 3,17a-dihydroxypregnane 11,20 dione, in the presence of an acid catalyst at a temperature between about twenty and about 200 degrees centigrade, to cause conversion of the ZO-keto group to a 20-ketal group, and (2) reducing the ll-keto group of the ketal thus-formed with lithium aluminum hydride, in an organic solvent which is non-reactive under the conditions of the reaction at a temperature between about zero degrees centigrade and the reflux temperature of the reaction mixture, and (3) hydrolyzing the reduction product thus-obtained with a hydrolyzing agent selected from the group consisting of sulfuric acid and hydrochloric acid, and separating the thus-produced 3,11fi,17a-tl'ihydroxypregnan-20-one.

ROBERT H. LEVIN. BARNEY J. MAGERLEIN. ARTHUR R. HANZE.

No references cited. 

1. AN 11B,17A-DIHYDROXYPREGNAN-20 HAVING THE FOLLOWING GENERAL FORMULA: 